Deletion of a portion of the long arm of chromosome 9, del(q), is a recurring abnormality in acute myeloid leukemia (AML), frequently associated with the common translocation, t(8;21). The chimeric AML1-ETO1 transcription factor created by t(8;21) is insufficient for leukemogenesis. Our hypothesis is that a gene or genes on chromosome 9q cooperates with AML1-ETO in eukemogenesis. Our long-term goal is to identify the critical genes(s) affected on chromosome 9q, characterize their role in hematopoiesis and how they cooperate with other genes in leukemogenesis, and then translate these results into tools for prognostic and treatment stratification and the identification of targets for drug development. The studies proposed in Specific Aim #1 will determine if modulation of candidate gene activity by expression of full-length cDNAs or siRNAs affects the proliferation, survival, and differentiation of primary human CD34+ umbilical cord blood cells. The studies proposed in Specific Aim # 2 will evaluate the ability of candidate tumor suppressor genes in del(9q) AML to functionally cooperate with AML1-ETO in leukemogenesis using both in vitro and in vivo assays. The studies proposed in Specific Aim # 3 will employ a conditional gene targeting strategy to effect the loss of expression of the most promising candidate genes in the bone marrow of adult mice. We will use these mice to determine the role of these genes by themselves and in cooperation with AML1-ETO in hematopoiesis and leukemogenesis. This proposal is designed to identify a novel gene important in regulating hematopoiesis whose loss cooperates with other previously known genes to cause leukemia. One of the great challenges of cancer research is to determine how genes cooperate to cause cancer and translate this information to cancer cures. The information from this study will hopefully aid in the rational design of effective targeted therapies and may have relevance to the pathogenesis of other cancers.